Antibody to aquaporin-4 in the long-term course of neuromyelitis optica.
Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow-Robin spaces was described in patients with NMO [called NMO-IgG (NMO-immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO-IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO.
Jarius
S
S
Neurosciences Group, Weatherall Institute of Molecular Medicine, and Department of Neurology, John Radcliffe Hospital, University of Oxford, UK.
Aboul-Enein
F
F
Waters
P
P
Kuenz
B
B
Hauser
A
A
Berger
T
T
Lang
W
W
Reindl
M
M
Vincent
A
A
Kristoferitsch
W
W
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19 / Q000097:blood; D051401:Aquaporin 4 / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000276:immunology; D001379:Azathioprine / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000188:drug therapy / Q000276:immunology*; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D055815:Young Adult
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D051401:Aquaporin 4; D001323:Autoantibodies; D015415:Biomarkers; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069283:Rituximab; D001379:Azathioprine